Novel compositions and therapeutic methods using same

Title: Novel compositions and therapeutic methods using same.Abstract: The present invention includes compositions and methods for treating a subject in need of opioid therapy, wherein the opioid therapy produces or has the possibility of producing respiratory depression or a breathing control disorder in the subject. ...

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of, and claims priority to, U.S. application Ser. No. 12/910,490, filed Oct. 22, 2010, which application is incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

Normal control of breathing is a complex process that involves the body's interpretation and response to chemical stimuli such as carbon dioxide, pH and oxygen levels in blood, tissues and the brain. Breathing control is also affected by wakefulness (i.e., whether the patient is awake or sleeping). Within the brain medulla, there is a respiratory control center that interprets the various signals that affect respiration and issues commands to the muscles that perform the work of breathing. Key muscle groups are located in the abdomen, diaphragm, pharynx and thorax. Sensors located centrally and peripherally then provide input to the brain's central respiration control areas that enables response to changing oxygen requirements.

Normal respiratory rhythm is maintained primarily by the body's rapid response to changes in carbon dioxide levels (CO2). Increased CO2 levels signal the body to increase breathing rate and depth, resulting in higher oxygen levels and subsequent lower CO2 levels. Conversely, low CO2 levels can result in periods of apnea (no breathing) since the stimulation to breathe is absent. This is what happens when a person hyperventilates.

In addition to the role of the brain, breathing control is the result of feedback from both peripheral and central chemoreceptors, but the exact contribution of each is unknown.

There are many diseases in which loss of normal breathing rhythm is a primary or secondary feature of the disease. Examples of diseases with a primary loss of breathing rhythm control are apneas (central, mixed or obstructive; where the breathing repeatedly stops for 10 to 60 seconds) and congenital central hypoventilation syndrome. Secondary loss of breathing rhythm may be due to chronic cardio-pulmonary diseases (e.g., heart failure, chronic bronchitis, emphysema, and impending respiratory failure), excessive weight (e.g., obesity-hypoventilation syndrome), certain drugs (e.g., anesthetics, sedatives, anxiolytics, hypnotics, alcohol, and narcotic analgesics) and/or factors that affect the neurological system (e.g., stroke, tumor, trauma, radiation damage, and ALS). In chronic obstructive pulmonary diseases where the body is exposed to chronically low levels of oxygen, the body adapts to the lower pH by a kidney mediated retention of bicarbonate, which has the effect of partially neutralizing the CO2/pH respiratory stimulation. Thus, the patient must rely on the less sensitive oxygen-based system.

In particular, loss of normal breathing rhythm during sleep is a common condition. Sleep apnea is characterized by frequent periods of no or partial breathing. Key factors that contribute to these apneas include decrease in CO2 receptor sensitivity, decrease in hypoxic ventilatory response sensitivity (e.g., decreased response to low oxygen levels) and loss of “wakefulness.” Normal breathing rhythm is disturbed by apnea events, resulting in hypoxia (and the associated oxidative stress) and eventually severe cardiovascular consequences (high blood pressure, stroke, heart attack). Snoring has some features in combination with sleep apnea. The upper airway muscles lose their tone resulting in the sounds associated with snoring but also inefficient airflow, which may result in hypoxia.

The ability of a mammal to breathe, and to modify breathing according to the amount of oxygen available and demands of the body, is essential for survival. There are a variety of conditions that are characterized by or due to either a primary or secondary cause. Estimates for U.S. individuals afflicted with conditions wherein there is compromised respiratory control include sleep apneas (15-20 millions); obesity-hypoventilation syndrome (5-10 millions); chronic heart disease (5 millions); chronic obstructive pulmonary disease (COPD)/chronic bronchitis (10 millions); drug-induced hypoventilation (2-5 millions); and mechanical ventilation weaning (0.5 million).

Racemic 1-ethyl-4-(2-morphilinoethyl)-3,3-diphenyl-2-pyrrolidinone (commonly known as doxapram) is a known respiratory stimulant, marketed under the name of Dopram™.

Doxapram was first synthesized in 1962 and shown to have a strong, dose-dependent effect on stimulating respiration (breathing) in animals (Ward & Franko, 1962, Fed. Proc. 21:325). Administered intravenously, doxapram causes an increase in tidal volume and respiratory rate. Doxapram is used in intensive care settings to stimulate respiration in patients with respiratory failure and to suppress shivering after surgery. Doxapram is also useful for treating respiratory depression in patients who have taken excessive doses of opioid drugs such as buprenorphine and fail to respond adequately to treatment with naloxone. However, use of doxapram in the medical setting is hampered by several reported side effects. High blood pressure, panic attacks, tachycardia (rapid heart rate), tremor, convulsions, sweating, vomiting and the sensation of “air hunger” may occur upon doxapram administration. Therefore, doxapram may not be used in patients with coronary heart disease, epilepsy and high blood pressure.

The C-4 carbon in the structure of doxapram is a chiral center, and thus there are two distinct enantiomers associated with this molecule: the (+)-enantiomer and the (−)-enantiomer. The concept of enantiomers is well known to those skilled in the art. The two enantiomers have the same molecular formula and identical chemical connectivity but opposite spatial “handedness.” The two enantiomers are a mirror image of each other but are not superimposable.

Chiral molecules have the unique property of causing a rotation in the original plane of vibration of plane-polarized light. Individual enantiomers are able to rotate plane-polarized light in a clockwise (dextrorotary; the (+)-enantiomer) or counter clockwise (levorotatory; the (−)-enantiomer) manner. For a specific combination of solvent, concentration and temperature, the pure enantiomers rotate plane-polarized light by the same number of degrees but in opposite directions.

A racemic mixture or a “racemate” is a term used to indicate the mixture of essentially equal quantities of enantiomeric pairs. Racemic mixtures are devoid of appreciable optical activity due to the mutually opposing optical activities of the individual enantiomers. Apart from their interaction with polarized light, enantiomers may differ in their physical, chemical and pharmacology activities, but such differences between enantiomers are largely unpredictable. Recent attempts have been made to develop pure enantiomers as new drugs, based on previously marketed racemic drugs (Nunez et al., 2009, Curr. Med. Chem. 16(16):2064-74). Development of an individual enantiomer as a novel drug, based on the already used racemate, requires the de novo pharmacokinetic, pharmacological and toxicological characterization of the enantiomer, since its properties may differ substantially and unpredictably from those of the racemate.

There is a need in the art for a method of treating breathing control disorders or diseases. Such method should include the administration of a composition comprising a compound that restores all or part of the body's normal breathing control system in response to changes in CO2 and/or oxygen, and yet has minimal side effects. There is a further need for compositions and methods useful for treating a subject in need of opioid therapy, wherein opioid therapy produces or has the possibility of producing respiratory depression or a breathing control disorder. The present invention fulfills these needs.

BRIEF

SUMMARY

The invention includes a method of treating a subject in need of opioid therapy, wherein the opioid therapy produces or has the possibility of producing respiratory depression or a breathing control disorder. The method comprises administering to the subject an effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of (+)-doxapram, a deuterated derivative thereof, any salt thereof, and any combinations thereof. The method further comprises administering to the subject an effective amount of an opioid, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative thereof, a salt thereof or any combinations thereof.

In one embodiment, the compound is at least about 95% enantiomerically pure. In another embodiment, the compoundis at least about 97% enantiomerically pure. In yet another embodiment, the compound is at least about 99% enantiomerically pure. In yet another embodiment, the opioid comprises morphine, codeine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, meperidine, methadone, nalbuphine, butorphanol, buprenorphine, propoxyphene, pentazocine, dihydrocodeine, tapentadol, fentanyl, remifentanil, alfentanil, sufentanil, carfentanil, or any combinations thereof. In yet another embodiment, the subject is further administered at least one additional compound selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotinergic modulator, an ampakine, and any combinations thereof. In yet another embodiment, the composition is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject. In yet another embodiment, the composition is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route. In yet another embodiment, the administering of the compound takes place before or after the administering of the opioid to the subject. In yet another embodiment, the administering of the compound takes place within 6 hours of the administering of the opioid to the subject. In yet another embodiment, the compoundand the opioid are co-administered to the subject. In yet another embodiment, the compound and the opioid are co-formulated. In yet another embodiment, the composition further comprises a pharmaceutically acceptable carrier. In yet another embodiment, the subject is a mammal. In yet another embodiment, the mammal is human.

The invention also includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an opioid and a compound selected from the group consisting of (+)-doxapram, a deuterated derivative thereof, any salt thereof, and any combinations thereof, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative thereof, a salt thereof, or any combinations thereof. In one embodiment, the compound is at least about 95% enantiomerically pure. In another embodiment, the compound is at least about 97% enantiomerically pure. In yet another embodiment, the compound is at least about 99% enantiomerically pure. In yet another embodiment, the opioid comprises morphine, codeine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, meperidine, methadone, nalbuphine, butorphanol, buprenorphine, propoxyphene, pentazocine, dihydrocodeine, tapentadol, fentanyl, remifentanil, alfentanil, sufentanil, carfentanil, or any combinations thereof.

The invention also includes a method of preventing or treating a breathing control disorder or disease in a subject in need thereof. The method comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a deuterated derivative of (+)-doxapram orany salt thereof, wherein the composition is essentially free of a deuterated derivative of (−)-doxapram or any salt thereof.

In one embodiment, the deuterated derivative of (+)-doxapram or salt thereof is at least about 95% enantiomerically pure. In another embodiment, the deuterated derivative of (+)-doxapram or salt thereof is at least about 97% enantiomerically pure. In yet another embodiment, the deuterated derivative of (+)-doxapram or salt thereof is at least about 99% enantiomerically pure. In yet another embodiment, the breathing control disorder or disease is selected from the group consisting of respiratory depression, sleep apnea, apnea of prematurity, obesity-hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia, and hypercapnia. In yet another embodiment, the subject is further administered at least one additional compound useful for treating the breathing control disorder or disease. In yet another embodiment, the at least one additional compound is selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone and related compounds, a serotinergic modulator and an ampakine. In yet another embodiment, the composition is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject. In yet another embodiment, the subject is a human. In yet another embodiment, wherein the composition is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route.

The invention also includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof. The method comprises administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a deuterated derivative of (+)-doxapram or a salt thereof, wherein the composition is essentially free of a deuterated derivative of (−)-doxapram or a salt thereof.

In one embodiment, the deuterated derivative of (+)-doxapram or a salt thereof is at least about 95% enantiomerically pure. In another embodiment, the deuterated derivative of (+)-doxapram or salt thereof is at least about 97% enantiomerically pure. In yet another embodiment, the deuterated derivative of (+)-doxapram or salt thereof is at least about 99% enantiomerically pure. In yet another embodiment, the subject is further administered at least one additional compound useful for preventing destabilization of or stabilizing the breathing rhythm. In yet another embodiment, the at least one additional compound is selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, a serotinergic modulator and an ampakine. In yet another embodiment, the composition is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device. In yet another embodiment, the subject is a mammal. In yet another embodiment, the mammal is human. In yet another embodiment, the composition is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route.

The invention also includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a deuterated derivative of (+)-doxapram or any salt thereof, wherein the composition is essentially free of a deuterated derivative of (−)-doxapram or a salt thereof. In one embodiment, the deuterated derivative of (+)-doxapram or salt thereof is at least about 95% enantiomerically pure. In another embodiment, the deuterated derivative of (+)-doxapram or salt thereof is at least about 97% enantiomerically pure. In yet another embodiment, the deuterated derivative of (+)-doxapram or salt thereof is at least about 99% enantiomerically pure.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention, there are depicted in the drawings certain embodiments of the invention. However, the invention is not limited to the precise arrangements and instrumentalities of the embodiments depicted in the drawings.

FIG. 1 is a graph illustrating the minute ventilation (in ml/min units), as indicated by the maximum peak response, for different intravenous doses of (+)-doxapram, (−)-doxapram and racemic doxapram.

FIG. 2 is a graph illustrating the effects of (+)-doxapram, (−)-doxapram and a vehicle control on opioid-induced respiratory depression, measured as minute ventilation (ml/min), in the rat. The opioid used was morphine.

FIG. 3 is a graph illustrating the pCO2 (in mm Hg) in the rat upon administration of morphine (10 mg/kg) followed by an infusion of (curve A) vehicle, (curve B) (−)-doxapram, (curve C) (+)-doxapram, or (curve D) racemic doxapram. The infusion duration is indicated by the bar.

FIG. 4 is a graph illustrating the O2 saturation (in %) in the rat upon administration of morphine (10 mg/kg) followed by an infusion of (curve A) vehicle, (curve B) (−)-doxapram, (curve C) (+)-doxapram, or (curve D) racemic doxapram. The infusion duration is indicated by the bar.

FIG. 5 is a graph illustrating the effects of (+)-doxapram, (−)-doxapram and a vehicle control on the hypoxic ventilatory response, measured as minute ventilation (ml/min), to 12% O2 in the rat.

FIG. 7, comprising FIGS. 7A-7B, is a series of traces illustrating the effects of 30 mg/kg IV (−)-doxapram (from top to bottom in FIG. 7A) respiratory flow (in ml/min), blood pressure (in mm Hg), inspiratory volume (in ml/min), and (from top to bottom in FIG. 7B) expiratory volume (in ml/min), respiratory rate (in breaths/min), and minute ventilation (in ml/min) in the rat. The y-axis indicates the parameter in question, and the x-axis is time (min). The dotted line indicates IV bolus administration (30 mg/kg) of (−)-doxapram.

FIG. 8 is a graph illustrating the effects of (−)-doxapram on blood pressure (in mm Hg) in the rat (as a detail enlargement of the corresponding curve illustrated in FIG. 7). The y-axis is blood pressure, and the x-axis is time. The dotted line indicates start of administration of (−)-doxapram (30 mg/kg IV bolus).

FIG. 9 is a set of graphs illustrating the IV pharmacokinetics of a 20-minute infusion (from 15 minutes to 35 minutes) of 3 mg/kg/min IV (+)-doxapram and (−)-doxapram. The upper panel pharmacokinetic data was plotted on a linear y-axis, the lower panel represents the same data plotted on a log y-axis. The plasma exposures of the two enantiomers have directly comparable time course, maximum concentration and exposure (AUC), thus demonstrating there is no appreciable difference between the pharmacokinetics properties of the two enantiomers.

DETAILED DESCRIPTION

In one aspect, the present invention relates to the unexpected discovery that the (+)-enantiomer of doxapram or a deuterated derivative thereof displays most or all the desired beneficial pharmacological activity associated with the racemic doxapram (which is marketed and used for the treatment of respiratory diseases and disorders).

In another aspect, the present invention relates to the unexpected discovery that the (−)-enantiomer of doxapram or a deuterated derivative thereof is essentially devoid of activity in stimulating ventilation or reversing respiratory depression, and moreover produces a number of acute side effects that were not detected as the same doses with (+)-doxapram or a deuterated derivative thereof, such as hunching posture, increased urination and defecation, clonic movements and other seizure-like behaviors, pronounced drops in mean arterial blood pressure, and production of cardiac arrhythmias and death.

The present invention includes a pharmaceutical composition comprising the (+)-enantiomer of 1-ethyl-4-(2-morphilinoethyl)-3,3-diphenyl-2-pyrrolidinone, also known as (+)-doxapram, a deuterated derivative thereof, or a salt thereof and a pharmaceutically acceptable carrier, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative thereof, or a salt thereof.

The present invention also includes a method of treating a breathing control disease or disorder in a subject in need thereof. The breathing control disease or disorder includes, but is not limited to, respiratory depression (induced by anesthetics, sedatives, anxiolytic agents, hypnotic agents, alcohol, and analgesics), sleep apnea, apnea of prematurity, obesity-hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, hypoxia and hypercapnia. The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising (+)-doxapram, a deuterated derivative thereof, or a salt thereof, and a pharmaceutically acceptable carrier, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative thereof, or a salt thereof.

The present invention also includes a method of treating a subject in need of opioid therapy, wherein opioid therapy produces or has the possibility of producing respiratory depression or a breathing control disorder, wherein the subject is administered an opioid and a composition comprising (+)-doxapram, a deuterated derivative thereof, a salt thereof, or any mixtures thereof, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative thereof, a salt thereof, or any mixtures thereof. In one embodiment, the opioid and (+)-doxapram, or deuterated derivative thereof, are administered separately to the subject. In another embodiment, the opioid and (+)-doxapram, or deuterated derivative thereof, are co-administered to the subject. In yet one embodiment, the opioid and (+)-doxapram, or deuterated derivative thereof, are co-formulated and co-administered to the subject.

Definitions

As used herein, each of the following terms has the meaning associated with it in this section.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, animal pharmacology, and organic chemistry are those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

A “subject”, as used therein, can be a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the subject is human.

As used herein, the term “doxapram” refers to 1-ethyl-4-(2-morphilinoethyl)-3,3-diphenyl-2-pyrrolidinone, or a salt thereof. Unless otherwise noted, “doxapram” refers to racemic doxapram, which comprises an essentially equimolar mixture of the two enantiomers of doxapram (the (+)-enantiomer and the (−)-enantiomer).

As used herein, the “(+)-doxapram” and “(−)-doxapram” enantiomers are defined in terms of the order in which they are eluted from chiral HPLC column, defined as: (a) a CHIRALPAK® AY 20μ column, with 3 cm internal diameter×25 cm length, using ethanol with 0.2% DMEA (dimethylethylamine) and CO2 as mobile phase, in a ratio of 15:85, with a flow rate of 85 g/min, a column temperature of 35° C., and UV detection at 220 nm; or (b) a CHIRALPAK® AY-H 5μ column, with 3 cm internal diameter×25 cm length, using ethanol with 0.2% DMEA and CO2 as mobile phase, in a ratio of 15:85, with a flow rate of 85 g/min, a column temperature of 35° C., and UV detection at 220 nm. Under either condition, the (−)-doxapram enantiomer has a shorter elution/retention time from the column than the (+)-doxapram enantiomer. The nomenclature “(+)-doxapram” should not be construed to imply that this enantiomer rotates the vibrational plane of plane-polarized light in a clockwise manner under all possible combinations of solvent, temperature and concentration. Similarly, the nomenclature “(−)-doxapram” should not be construed to imply that this enantiomer rotates the vibrational plane of plane-polarized light in a counter-clockwise manner under all possible combinations of solvent, temperature and concentration.

As used herein, the term “enantiomeric purity” of a given enantiomer over the opposite enantiomer indicates the excess % of the given enantiomer over the opposite enantiomer, by weight. For example, in a mixture comprising about 80% of a given enantiomer and about 20% of the opposite enantiomer, the enantiomeric purity of the given enantiomer is about 60%.

As used herein, the term “essentially free of” as applied to a given enantiomer in a mixture with the opposite enantiomer indicates that the enantiomeric purity of the given enantiomer is higher than about 80%, more preferably higher than about 90%, even more preferably higher than about 95%, even more preferably higher than about 97%, even more preferably higher than about 99%, even more preferably higher than about 99.5%, even more preferably higher than about 99.9%, even more preferably higher than about 99.95%, even more preferably higher than about 99.99%. Such purity determination may be made by any method known to those skilled in the art, such as chiral HPLC analysis or chiral electrophoresis analysis.

In a non-limiting embodiment, the following terminology used to report blood gas measurements is well known to those skilled in the art and may be defined as such: minute ventilation (MV) is a measure of breathing volume per unit time and is given herein as ml/min; pCO2 is partial pressure of carbon dioxide (gas) in (arterial) blood measured in mmHg (millimeters of Hg units); pO2 is partial pressure of oxygen (gas) in (arterial) blood measured in mmHg (millimeters of Hg units); saO2 is the percentage of oxygen saturation (dissolved oxygen gas) which correlates to the percentage of hemoglobin binding sites in the bloodstream occupied by oxygen.

As used herein, the term ED50 refers to the effective dose that produces a given effect in 50% of the subjects.

As used herein, a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal\'s health continues to deteriorate.

As used herein, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal\'s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal\'s state of health.

As used herein, an “effective amount” or “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered. The term to “treat,” as used herein, means reducing the frequency with which symptoms are experienced by a patient or subject or administering an agent or compound to reduce the severity with which symptoms are experienced.

As used herein, “treating a disease or disorder” means reducing the frequency with which a symptom of the disease or disorder is experienced by a patient. Disease and disorder are used interchangeably herein.

As used herein, the term “adverse events” (AEs) or “adverse effects” refer to a change in normal behavior or homeostasis and refers to observed or measured effects in animals such as hunching posture, increased urination and defecation, clonic movements and other seizure-like behaviors, pronounced drops in mean arterial blood pressure, production of cardiac arrhythmias and death. Adverse effects or adverse events may also refer to respiratory depression caused by opioids.

As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

Compositions of the Invention

The invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and (+)-doxapram, a deuterated derivative thereof, or a salt thereof, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative thereof, or a salt thereof.

The invention also includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier, an opioid and (+)-doxapram, a deuterated derivative thereof, or a salt thereof, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative thereof, or a salt thereof.

Racemic doxapram or a salt thereof may be prepared using any of the methods disclosed in the chemical literature. As a non-limiting example, the synthetic scheme illustrated below may be used to prepare racemic doxapram.

(+)-Doxapram, deuterated derivative thereof or a salt thereof that is essentially free of (−)-doxapram, a deuterated derivative thereof or a salt thereof may be prepared by chiral resolution of racemic doxapram, using a method such as chiral chromatography (in a non-limiting example, chiral HPLC). In a non-limiting example, (+)-doxapram or a salt thereof, which is essentially free of (−)-doxapram or a salt thereof, may be isolated from racemic doxapram in >99% enantiomeric excess using supercritical fluid chromatography (SFC) and a suitable chiral column, such as a CHIRALPAK® AY, 20μ (micron), 30×250 mm column with EtOH with 0.2% DMEA (dimethylethylamine) and CO2 (15:85) as mobile phase. Alternatively, the same separation may be performed on a CHIRALPAK® AY-H, 5μ column, 4.6×250 mm column with EtOH with 0.2% DMEA:CO2 (15:85) as mobile phase. Doxapram enantiomers may also be analyzed using a CHIRALCEL® OJ-H, 5μ with 90% hexane—8% isopropanol—2% methanol—0.1% DMEA. The columns are operated according to the manufacturer\'s instructions.

Methods of the Invention

A composition comprising (+)-doxapram, a deuterated derivative thereof, or a salt thereof, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative thereof, or a salt thereof, is useful within the methods of the invention. A composition comprising an opioid and (+)-doxapram, a deuterated derivative thereof, or salt thereof, wherein the composition is essentially free of (−)-doxapram, deuterated derivative thereof, or salt thereof, is also useful within the methods of the invention.

In one aspect, the present invention relates to the unexpected discovery that the (+)-enantiomer of doxapram, deuterated derivative thereof, or salt thereof displays most or all the desired beneficial pharmacological activity associated with the ventilatory stimulant effects, and positive effects on arterial blood gases, of racemic doxapram (which is marketed and used for the treatment of respiratory diseases and disorders).

In another aspect, the present invention relates to the unexpected discovery that the (−)-enantiomer of doxapram, deuterated derivative thereof, or salt thereof is essentially devoid of activity as a ventilatory or respiratory stimulant, but unexpectedly produces adverse side effects, such as hunching posture, increased urination and defecation, clonic movements and other seizure-like behaviors, pronounced drops in mean arterial blood pressure, production of cardiac arrhythmias and death.

The invention includes a method of treating a subject in need of opioid therapy, wherein opioid therapy produces or has the possibility of producing respiratory depression or a breathing control disorder. The method comprises administering to the subject an effective amount of a pharmaceutical composition comprising (+)-doxapram, a deuterated derivative thereof, or a salt thereof. The method further comprises administering to the subject an effective amount of an opioid, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative thereof, or a salt thereof.

In one embodiment, the (+)-doxapram, deuterated derivative thereof, or salt thereof is at least about 95% enantiomerically pure. In another embodiment, the (+)-doxapram, deuterated derivative thereof, or salt thereof is at least about 97% enantiomerically pure. In yet another embodiment, the (+)-doxapram, deuterated derivative thereof, or salt thereof is at least about 99% enantiomerically pure. In yet another embodiment, the opioid comprises morphine, codeine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, meperidine, methadone, nalbuphine, butorphanol, buprenorphine, propoxyphene, pentazocine, dihydrocodeine, tapentadol, fentanyl, remifentanil, alfentanil, sufentanil, carfentanil, or any combinations thereof. In yet another embodiment, the subject is further administered at least one additional compound selected from the group consisting of acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotinergic modulator, an ampakine, and any combinations thereof. In yet another embodiment, the composition is administered in conjunction with the use of a mechanical ventilation device or positive airway pressure device on the subject. In yet another embodiment, the composition is administered to the subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal or intravenous route. In another embodiment, the composition further comprises a pharmaceutically acceptable carrier. In yet another embodiment, the subject is a mammal. In yet another embodiment, the mammal is human.

The invention contemplates administering the opioid and (+)-doxapram, or deuterated derivative thereof, to the subject separately (i.e., the administering of (+)-doxapram or a salt thereof takes place before or after the administering of the opioid to the subject). In one embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 6 hours of the administering of the opioid to the subject. In another embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 5 hours of the administering of the opioid to the subject. In yet another embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 4 hours of the administering of the opioid to the subject. In another embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 3 hours of the administering of the opioid to the subject. In another embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 2 hours of the administering of the opioid to the subject. In another embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 1 hour of the administering of the opioid to the subject. In another embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 45 minutes of the administering of the opioid to the subject. In another embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 30 minutes of the administering of the opioid to the subject. In another embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 15 minutes of the administering of the opioid to the subject. In another embodiment, the administering of (+)-doxapram, deuterated derivative thereof, or salt thereof takes place within 5 minutes of the administering of the opioid to the subject.

The invention also contemplates co-administering (+)-doxapram, deuterated derivative thereof, or salt thereof and the opioid to the subject. In one embodiment, the (+)-doxapram, deuterated derivative thereof, or salt thereof and the opioid are co-formulated. (+)-Doxapram, deuterated derivative thereof, or salt thereof and the opioid may be co-formulated using any pharmaceutically acceptable carrier known to those skilled in the art.

The experiments disclosed in the present invention suggest that a composition comprising (+)-doxapram, deuterated derivative thereof, or salt thereof, wherein the composition is essentially free of (−)-doxapram, deuterated derivative thereof, or salt thereof, may be administered to a subject who is prone to or suffers from a breathing control disorder or disease in order to prevent, treat or mitigate the breathing control disorder. Administration of a composition comprising (+)-doxapram, deuterated derivative thereof, or salt thereof, wherein the composition is essentially free of (−)-doxapram, deuterated derivative thereof, r a salt thereof, is unexpectedly advantageous over administration of racemic doxapram or a salt thereof, because (+)-doxapram, deuterated derivative thereof, or salt thereof has most or all the desired beneficial pharmacological respiratory stimulant activity, together with positive effects on arterial blood gases, associated with racemic doxapram but with significantly reduced adverse side effects compared to administration of racemic doxapram or a salt thereof, due to the presence of the (−)-enantiomer, which has no specific ventilatory activity but produces side effects and toxicity.

In one aspect, the present invention includes a method of preventing or treating a breathing control disorder or disease in a subject in need thereof. The method comprises administering to the subject an effective amount of a pharmaceutical composition comprising (+)-doxapram, deuterated derivative thereof, or salt thereof and a pharmaceutically acceptable carrier, wherein the composition is essentially free of (−)-doxapram, deuterated derivative thereof, or a salt thereof.

In one embodiment, the enantiomeric purity of the (+)-doxapram, deuterated derivative thereof, or salt thereof is at least about 90%. In another embodiment, the enantiomeric purity of the (+)-doxapram, deuterated derivative thereof, or salt thereof is at least about 95%. In yet another embodiment, the enantiomeric purity of the (+)-doxapram, deuterated derivative thereof, or salt thereof is at least about 97%. In yet another embodiment, the enantiomeric purity of the (+)-doxapra, deuterated derivative thereof, or salt thereof is at least about 99%. In yet another embodiment, the enantiomeric purity of the (+)-doxapram, deuterated derivative thereof, or salt thereof is at least about 99.5%. In yet another embodiment, the enantiomeric purity of the (+)-doxapram, deuterated derivative thereof, or salt thereof is at least about 99.9%. In yet another embodiment, the enantiomeric purity of the (+)-doxapram, deuterated derivative thereof, or a salt thereof is at least about 99.95%. In yet another embodiment, the enantiomeric purity of the (+)-doxapram, deuterated derivative thereof, or salt thereof is at least about 99.99%.

The invention also contemplates a pharmaceutical composition comprising a deuterated derivative of (+)-doxapram or a salt thereof, wherein the composition is essentially free of (−)-doxapram, a deuterated derivative of (−)-doxapram, or a salt thereof. In one embodiment, the deuterated derivative of (+)-doxapram has better or equivalent properties as compared to (+)-doxapram, such as but not limited to pharmacokinetics, absorption, metabolism, activity or side effects. The invention contemplates any deuterated derivative of (+)-doxapram, varying from 1-30 deuteriums. For example, the deuterated derivative of (+)-doxapram may have 0-5 deuteriums in the ethyl group, 0-10 deuteriums on the phenyl groups, 0-3 deuteriums on the pyrrolidinone ring, 0-4 deuteriums in the ethylene linker, and 0-8 deuteriums on the morpholino group.

The invention also includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a deuterated derivative of (+)-doxapram or any salt thereof, wherein the composition is essentially free of a deuterated derivative of (−)-doxapram or a salt thereof. In one embodiment, the deuterated derivative of (+)-doxapram or any salt thereof is at least about 95% enantiomerically pure. In another embodiment, the deuterated derivative of (+)-doxapram or any salt thereof is at least about 97% enantiomerically pure. In yet another embodiment, the deuterated derivative of (+)-doxapram or any salt thereof is at least about 99% enantiomerically pure.

Non-limiting examples of deuterated derivatives of doxapram useful within the compositions and methods of the invention are illustrated below:

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